Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
immunosuppressive conditions. The conditions are highly likely to impact the outcome of the
immune response.
(i) Inflammatory conditions
A parallel infection or adjuvant administration can induce an inflammatory microenvironment
at the time of vaccination. Consequently, the immune response induced following injection
may qualitatively different because of the impact of existing inflammatory signals on local
immune and/or stromal cells (Wilson et al., 2006). Similarly, patients that have a chronic
disease might respond differently to vaccination because their immune system is being
continually stimulated, which critically can lead to exhaustion of the immune system (Frebel
et al., 2010).
(ii) Immunosuppressive conditions
The investigation of cancer vaccines represents an interesting and informative perspective that
exemplifies the impact of pre-existing conditions on the effectiveness of immune response.
Many well-characterized mouse studies have investigated prophylactic vaccination, which
refers to the vaccination of the animal against tumor antigens prior to tumor challenge. Yet, in
most physiologic cases, the tumor will already be present at the time point that the patient
would be treated with cancer vaccine. Thus, the focus needs to be on the development of
therapeutic vaccination strategies. The presence of a tumor makes a dramatic difference, as
tumors are known to induce an immunosuppressive microenvironment, as well as have a
limited access to immune cells (Lesterhuis et al., 2011). Both factors would critically impact
the response to a vaccine. To circumvent the impact of the tumor on the effectiveness of the
immune response, patients can be treated at very early stages when the immune system is still
competent or therapies can be modified by combining the vaccine with other treatments that
will inhibit tumor-mediated immunosuppression.
(iii) Combination of treatments
To optimize treatment efficiency, several approaches are often combined: for example,
adjuvant mixed with peptide vaccine, chemotherapy or radiotherapy administered in parallel
of cancer vaccine. These additional treatments modify the microenvironment and may
enhance the immune response despite tumor-mediated immune suppression. Importantly, the
timing for these different treaments remains to be tested, as it has been observed that targeted
therapies applied before or after the administration of a cancer vaccine do not have the same
impact on disease progression (Vanneman and Dranoff, 2012). Similarly, the injection of
adjuvant prior to immunization has been shown to completely inhibit subsequent T cell
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